Bone grafts in the form of non-woven, woven, braided, or knitted synthetic calcium phosphates (CaP) show potential as a resorbable scaffolding supporting the growth of new bone in applications such as spinal fusion, long bone fractures, non-union fractures, bone defects, and hip revisions. In known devices, the rate at which the device resorbs in the body is typically controlled by the surface area or composition of the graft. The ability to control the resorption rate of the scaffold by orders of magnitude without having to change the scaffold's composition or morphology may be advantageous in optimizing bone growth into the scaffold.
Bone grafts are used in the repair of significant fractures, the treatment of skeletal tumors, spinal fusion, and the reconstruction of failed total arthroplasties. Autogenous bone, or autograft, is harvested from another location in the patient, and used as the graft. Autograft performs very well in the applications cited above. The disadvantages of autograft include the limited supply of excess bone in the patient, as well as the inherent risks of morbidity and recovery pain resulting from a second surgery site. Allograft, bone taken from another human, has the advantage of being in larger supply than autograft bone. However, the greater immunogenic response of allograft, and risk of viral contamination or risk of transmission of live virus to the recipient, have led to the decline in use of allograft bone as a bone graft material. Xenograft, or bone grafts taken from another species, often elicits acute antigenic responses. In the vast majority of cases, xenograft fails in its role as a graft material.
Synthetic bone graft materials have been described in “Bone Graft and Bone Graft Substitutes: A Review of Current Technology and Applications”; Damien and Parsons; J. Applied Biomaterials, Vol. 2, 1991, pages 187–208, which is incorporated herein by reference. The ideal graft should be able to support a load equivalent to the bone that is being replaced, so that the newly formed bone can remodel to the same quality and dimensions of the original bone that is being replaced. The ideal graft is also osteoactive, enhancing the formation of new bone. This is achieved both by the chemical nature of the material, as well as the structure, or architecture of the graft. Structurally, the graft needs to be porous to allow for ingrowth of the new bone. Though no optimal pore size has been established, the size of the pores required for good bone growth is between 100 and 500 microns. The ability to tailor the pore size and distribution is also viewed as a method of enhancing bone growth. In addition, the ideal graft material will be resorbed into the body at a rate equivalent to the rate at which the new bone is being formed. If the graft resorbs too rapidly, gaps and/or stress concentrations can result. If the resorption rate is too slow, the graft may inhibit the formation of new bone.
Bone grafts come in a variety of physical forms. These include, but are not limited to, loose particles, particles bound in polymer or other carrier material (a paste), ceramic precursors that react when blended together (calcium phosphate cements), porous solids, loose fiber constructs (such as felts), or textile processed fibers (weaves, braids, or knits).
The disadvantages of using loose particles as a bone graft include the tendency of the particles to either migrate away from the defect site in bodily fluids, or settle (or pack tightly) into the defect. Particle migration from the site results in possible tissue irritation and undesired tissue response in the regions where the particles eventually settle. Particle settling results in two issues. First, when the particles pack together, the pore size is reduced in the graft to less than 100 μm. This pore size does not allow the migration and ingrowth of cells into the graft. Particle settling also results in an inability to control the pore size and distribution in these systems. The size of the particles and how they pack together determine the size and distribution of pores in these types of grafts. Since settling is not controllable, there is no ability to use graft architecture to control new bone growth into the graft.
Particle migration and settling problems have been mitigated to some extent by the use of synthetic or natural matrix materials, including polymers such as PMMA, polysulfone (PS), or polyethylene (PE), which are not resorbable, and ceramics, such as plaster of Paris. Particles have also been enclosed in tubes of resorbable polymers, such as collagen or polyglycolide. The size and distribution of pores in these types of grafts are also not controllable. The size of the particles, how they pack together, and the space between them caused by the carrier matrix determine the distribution. As with loose particles, there is limited ability to use graft architecture to control new bone growth into the graft.
For bone grafts in the form of cements, there is also a limited ability to control the pore size and distribution. Pore creating agents may be put into the cement prior to its formation. However, the size and distribution of pores are determined by the size, form, and concentration of the agent, resulting in the inability to use graft architecture to control new bone growth into the graft. This inability to control pore size and distribution also results in limits in load support capability. A random distribution of pores results in a random distribution of defects in the structure and associated low load support capability.
Control of the pore size and distribution in porous solid bone grafts is also limited. Porous solid bone grafts have been formed using the replamine process on naturally occurring coral. Here, the pore size and distribution are limited to that of the species of coral used. Defect location is also uncontrollable, lowering the load support capability of the graft in a fashion similar to that discussed above for cements. Pore creating agents may also be put into a ceramic prior to its formation. However, as is the case with cements, the size, form, and concentration of the agent determine the size and distribution of pores.
Bone grafts in the form of textile architectures, such as weaves, braids, or knits, have advantages over the other forms of bone grafts. Textile technology may by used to precisely place the fibers in a desired location in space, allowing for a large degree of control in the size and distribution of pores in the bone graft structure.
Tagai et al., in U.S. Pat. Nos. 4,820,573, 4,735,857, and 4,613,577, disclose a glass fiber for the filling of a defect or hollow portion of a bone. In this case, the calcium phosphate glass fiber may be in the form of short fibers, continuous fiber, or woven continuous fibers.
Though bone grafts in the textile forms address the limitations of particulate or solid bone grafts, one area not addressed is that of graft resorption rate. As described above, an ideal graft material will be resorbed into the body at a rate equivalent to the rate at which the new bone is being formed. Fast or slow resorption results may inhibit the formation of new bone or create gaps and/or stress concentrations in the native tissue.
An implant that slowly disappears and is replaced by native tissue, is said to be resorbed into the body. This resorption is a biological process in which the body breaks down a material into simpler components either chemically or physically. These simpler components are either soluble in bodily fluids, or digestible in cells such as macrophages. The degradation products are chemical compounds that are not toxic, and can easily be incorporated into the structure of the body or excreted.
The effects of both biological and physiochemical material properties of calcium phosphate ceramics on the rate at which bone grafts are resorbed into the body has been described in “Biodegradation and Bioresorption of Calcium Phosphate Ceramics”; Legeros; Clinical Materials, Vol. 14, 1993, pages 65–88, which is incorporated herein by reference. Biological factors affecting the degree and rate of resorption include age, implantation site, metabolic activity, diseased states, and the types of cells involved. The physiochemical parameters that affect resorption include the factors affecting the extent of material dissolution, such as physical form, density, porosity, composition and crystallinity.
A key parameter for determining the effect of physical form on the rate at which the graft is resorbed is the ratio of the surface area of the graft to its volume. For a given composition, as the surface to volume ratio increases, the resorption rate increases. For example, a porous graft will resorb significantly faster than a solid graft of equivalent volume. Fine particles resorb at a higher rate than course particles. A loosely woven fibrous structure resorbs at a higher rate than a tightly knitted structure of the same volume.
In U.S. Pat. No. 5,429,996, Kaneko disclosed a glass fiber/wool bone graft composed of SiO2—NaO2—CaO—B2O3—CaF2—P2O5, where dissolution rate is controlled by the diameter of the glass fiber. This graft was demonstrated to work in the treatment of periodontal disease. U.S. Pat. No. 4,867,779 (Meunier et al.) discussed a particulate or fibrous glass agricultural product composed of SiO2—K2O—CaO—MgO—Fe2O3—B2O3—MnO—ZnO—CuO—MoO3—Na2O—Al2O3—P2O5—SO3, where dissolution rate is controlled by th specific surface area of the fibers or particles. The preferred embodiment of their invention stated a most preferable specific surface area of 0.3 m2/gm. The limit of both of these concepts is the difficulty involved in making the number of sizes required to control dissolution rate over a wide range.
The rate at which bone grafts are resorbed into the body is also a function of the composition of the material composing the graft. There is a great deal of prior work discussing compositional effects on dissolution rate in calcium phosphate ceramics and glasses. A good review for ceramics is found in Structure and Chemistry of Apatites and Other Calcium Orthophosphate; Elliot; Studies in Inorganic Chemistry, Vol. 18, 1994. For phosphate glasses, a review can be found in Inorganic Calcium Phosphate glasses; Ropp; Studies in Inorganic Chemistry, Vol. 15, 1992. Both reviews are incorporated herein by reference.
In U.S. Pats. Nos. 3,897,236, 3,930,833, and 3,958,973, (all to Roberts), both the rate of ion release and the solubility of soil feed glasses composed of a variety of metal oxides are controlled by the level of some of the metal oxides in the glass. These include SiO2, K2O, CaO, B2O3, and Na2O.
Drake, in a series of patents (U.S. Pat. Nos. 4,123,248, 4,148,623, and 4,350,675), disclosed controlled release glass fertilizers composed of oxides of alkaline, Group II & Group III metals and P2O5. In these glasses, the release of nutrients was controlled by the rate of dissolution of the glass, which in turn was controlled by the weight percents of the components of the glass. In U.S. Pat. No. 4,645,749, Drake discussed CaO—Na2O—P2O5 glasses for the preparation of analytical solutions, where the release of sodium ions is controlled by the ratio of calcium to phosphorous in the glass. Finally, Drake and Brocklehurst, in U.S. Pat. No. 4,678,659, disclosed a therapeutic device for oral administration to the alimentary canal, composed of soluble phosphate glasses. Here, the solubility of the glass is controlled by the ratio of metal oxides composing the glass, and is tailored to be more soluble in low pH conditions, and less soluble at higher pH conditions.
Other disclosures of water soluble phosphate-based glasses for biological application, include U.S. Pat. Nos. 5,721,049, 5,645,934, and 5,468,544 (all to Marcolongo et al.), U.S. Pat. Nos. 5,252,523, 5,071,795, and 4,940,677 (all to Beall et al.), U.S. Pat. No. 4,612,923, (to Kronenthal), U.S. Pat. No. 4,482,541, (to Telfer et al.), and U.S. Pat. No. 4,437,192, (to Fujia et al.). In each case, the rate at which the glass body breaks down, or dissolves, is controlled by the ratio of the metal oxides in the compositions.
Still other works cite water soluble mineral or glass fibers for use as degradable insulation or fireproofing, where dissolution rate is controlled by the ratio of the metal oxides in the compositions. These include phosphate-based compositions, such as disclosed in U.S. Pat. No. 5,843,854, (to Karppinen et al.), U.S. Pat. No. 5,250,488, (to Theolan et al.), and U.S. Pat. No. 5,108,957, (to Cohen et al.), as well as nonphosphate-based compositions, such as U.S. Pat. No. 5,401,693, (to Bauer et al.), U.S. Pat. No. 5,332,699, (to Olds et al.), and U.S. Pat. No. 5,055,428, (to Porter).
In all of the above cited disclosures, the composition was used as a method of controlling the rate of dissolution. The limitation of this approach in the development of bone graft materials with controlled pore size and distribution is that if one desires to have grafts with a number of different dissolution rates, one is required to melt and spin a large number of different material compositions. The different material compositions have associated different degrees of biocompatibility, creating a situation in which a material composition having a less than optimal biocompatibility may be selected in order to achieve a desired dissolution rate.
The atmosphere under which the materials have been melted is also known to alter the dissolution rate of phosphate-based glasses and glass-ceramics. In U.S. Pat. No. 5,609,660, (to Francis et al.), the dissolution rate of magnesium phosphate glass was reduced by a factor of two by exposing the glass, in particulate form, to a nitriding environment. U.S. Pat. No. 5,215,563 (to LaCourse et al.) teaches that by melting an iron phosphate glass under a high oxygen environment, the dissolution rate can be reduced by thirty-three percent. Though these concepts are an improvement over the earlier methods of altering the composition of the glass, the range of dissolution rates possible from these teachings is small. In the present invention, resorption rates over a wide (order of magnitude) range are made possible by altering a step in the glass fiber processing.
Control of dissolution rates in phosphate glasses have also been seen by changing the stress state of the glass. This has been shown in U.S. Pat. No. 3,640,827 (to Lutz), where the dissolution rate of 9-mm spheres of sodium phosphate glass was changed by an order of magnitude by heat treating the glass below its melting point (annealing). Although Lutz '827 teaches that an order of magnitude change in dissolution can be achieved by annealing, it is limited to glass forms with dimensions significantly greater than those of interest in forming fibrous scaffolds composed of phosphate glass fibers with diameters on the order of 1–50 μm. Choueka et al., in “Effect of Annealing Temperature on the Degredation of Reinforcing Fibers for Absorbable Implants”; J. Applied Biomaterials, Vol. 2, 1991, pages 187–208, which is incorporated herein by reference, reports that the dissolution rate of a CaO—ZnO—Fe2O3—P2O5 glass fibers (10–20 μm in diameter) can be reduced by half by annealing below the melt temperature.
Finally, Ropp, in Inorganic Calcium Phosphate Glasses; Studies in Inorganic Chemistry, Vol. 15, 1992, teaches that for phosphate glasses, an increase in the time that the glass is held above its melt temperature results in an decrease in the dissolution rate of the glass by up to an order of magnitude. Ropp's work was done with cast glass bars, not fine (<100 μm diameter) glass fibers fabricated by melt drawing and pulling which are incorporated in bone graft textiles.
In summary, the prior art presents a number of synthetic bone grafts. The only grafts with tailored pore size and distributions are those composed of fibers formed into scaffold structures by textile operations. Tailored pore size is viewed as a method of enhancing bone growth. The effects of both biological and physiochemical material properties of calcium phosphate ceramics on the rate at which bone grafts are resorbed into the body have also been discussed. A known method of altering the resorption rate by an order of magnitude or more is by changing the composition of the scaffold. The ability to control the resorption rate of the scaffold by orders of magnitude without having to change the composition of the glass fibers composing the scaffold would be advantageous in matching the rate of bone growth into the scaffold with the dissolution of the scaffold.
It is therefore an object of the present invention to provide a bone graft in which the pore size and distribution are tailored to enhance bone growth, and the resorption rate of the scaffold is controlled over orders of magnitude by a simple and economical method.
Another object of this invention is to create structures to use as scaffolds for the in vitro or in vivo growth of human or animal tissue, such as bone or cartilage. These scaffolds can be used as implant materials for the replacement of defects or hollow portions of hard tissue resulting from external injury or surgical removal of hard tissue tumors. Their composition can be tailored such as to be resorbed by the body at a rate equivalent to the rate at which natural hard tissue grows into the above mentioned defects or hollow portions of hard tissue.
A still further object of this invention is the formation of laminated bioresorbable structures where each layer has controlled pore size and distribution for providing another degree of control for optimizing bone growth into the resorbable ceramic structure if the structure is used as bone graft.